Oxaliplatin is an international non-proprietary name for (SP-4-2)-[(1R,2R)-1,2-cyclohexandiamine-N,N′]-(oxalato-O,O′)-platinum(II) of the formula
which is a platinum metalopharmacum showing antitumour activity against some malignant solid tumours, including particularly malignant tumours of colon and rectum.
The structure of oxaliplatin, its pharmaceutical properties, and method for preparation thereof are described, for example, in the U.S. Pat. No. 4,169,846, according to which a boiling aqueous solution of (SP-4-2)-dichloro-[(1R,2R)-1,2-cyclohexanediamine-N,N′]platinum(II) is treated with 2 molar equivalents of an aqueous solution of a silver salt of a mineral acid, especially-silver nitrate, protected from light. After cooling of the reaction mixture, the mixture is filtered repeatedly to obtain a clear filtrate, which filtrate is then concentrated under reduced pressure in order to get a concentrate containing diaqua complex of platinum. To the concentrate, a salt of dicarboxylic acid, such as potassium oxalate, is added in an equimolar amount in relation to the starting platinum(II) complex, and the obtained solution is allowed to stand at room temperature. Subsequently, the solution is further concentrated under reduced pressure to obtain white crystalline precipitate. The obtained precipitate containing the required oxaliplatin is recrystallised from water solution. This process gives relatively low yields and is laborious, especially due to the fact that it is necessary to concentrate high volumes of filtrate and reaction mixture in individual steps. For this reason, the process is not suitable for carrying out on industrial scale. In the said patent document purity of oxaliplatin is not specified, particularly concerning the accompanying impurities originating from the process of preparation thereof, and the document does not state that the oxaliplatin obtained in this way would be suitable as an active compound for the preparation of pharmaceutical compositions, either.
The U.S. patent document No. U.S. Pat. No. 5,290,961 describes, inter alia, a method for preparation of oxaliplatin free or unreacted silver ions. According to this method, a platinum complex where platinum has the oxidation number II and which contains 1,2-cyclohexanediamine ligand and halogen ligands, is treated with a solution of at least two equivalents of silver. Subsequently, the precipitate of silver chloride or bromide is removed and a solution of sodium iodide or potassium iodide is added to the remaining solution, in order to convert the unreacted starting platinum compound, by-products of the starting compound and unreacted silver ion into insoluble form of iodine compounds, which are then removed, and, subsequently, a dibasic organic acid is added to the remaining solution of platinum complex. This method represents the last steps of a modified Dhar synthesis, according to which the starting compound is converted into a complex comprising iodine by the treatment with alkali metal iodide, then, after conversion into a relevant complex, the complex is treated with a soluble silver salt, and, subsequently, after removal of insoluble portion which contains essentially all present impurities including silver iodide, the produced aqua complex is converted into the corresponding product.
The international patent application No. WO 03/004505 describes oxaliplatin which can be used as a pharmacologically active compound. According to the said application, oxaliplatin is prepared in several steps: Initially potassium tetrachloroplatinate(II) is reacted with trans-(+)-1,2-cyclohexanediamine to obtain dichloro-(trans-(+)-1,2-cyclohexanediamine)-platinum(II), which is, after suspending in water, treated with a solution of silver nitrate in an amount of 2 equivalents in relation to the said platinum(II) complex, wherein a solution of potassium or sodium iodide and activated charcoal is optionally added to the obtained solution under stirring. After filtration, an alkali metal salt of oxalic acid is added to the filtrate, crystals of oxaliplatin are filtered off and washed up to five times with water having a pH 4.5 to 7.0. Oxaliplatin is purified by recrystallisation and crystals of oxaliplatin are collected on a filter, washed up to five times with water having a pH of 4.5 to 7.0. Although oxaliplatin is only slighly soluble in water at room temperature, it is obvious from Example 1 of said international patent application that washing with water causes losses of about 20% of oxaliplatin in one single operation only, i.e. during recrystallisation. This is a substantial drawback of this method for preparation of oxaliplatin.
Therefore, the purpose of the invention is to provide a method for preparation of a highly pure oxaliplatin, which method would be free of the drawbacks mentioned above.